Career Development Award
Yan Yang, PhD
MD Anderson Cancer Center
Houston
TX
In patients with EGFR-mutant NSCLC, tyrosine kinase inhibitors (TKIs) have been an effective treatment, but over time these patients develop resistance to TKIs, leading to tumor relapse. Dr. Yang’s project focuses on cancer cells called drug-tolerant persisters (DTPs), which are implicated in TKI resistance. A gene called HER3 is expressed in DTPs, and Dr. Yang will use specially engineered immune cells, called CAR-T cells, to target both HER3 and EGFR simultaneously. If successful, this approach would result in a bi-specific CAR-T cell that can be further evaluated in clinical trials.
Research Summary
In lung cancer patients with a specific genetic mutation in EGFR, certain drugs can be helpful, but over time, the cancer can learn to resist these drugs, making them less effective. We're focusing on a small group of tough cancer cells, called DTPCs, that survive the initial treatment because they might be the key to curing the cancer for good. We've noticed that a gene called HER3 is expressed more in these cells. We also have promising results from CAR-T cell therapy. It is a treatment using T cells, a type of immune cells, engineered with the chimeric antigen receptor (CAR) so they can find and destroy cancer cells. We've found that CAR-T cells targeting EGFR can kill DTPCs. We believe if we use these T cells to attack both HER3 and EGFR at the same time, we might have a better chance of killing off these stubborn cancer cells. To make sure this idea works, we'll first check if HER3 is indeed more expressed in these DTPCs in the lab and samples from patients. Then, we'll test our HER3-targeting CAR-T cells to see if they can kill these DTPCs. If that looks promising, we'll tweak the T cells to target both HER3 and EGFR and see if they work even better. If all goes well, we'll be able to make one of the first effective CAR-T cells to target both HER3 and EGFR and try them out in clinical trials.
Technical Abstract
In NSCLC patients harboring mutant EGFR, treatment with tyrosine kinase inhibitors (TKIs) has demonstrated efficacy. However, the emergence of resistance to EGFR TKIs remains a significant challenge, leading to disease progression. Targeting drug-tolerant persister cells (DTPCs), a rare subpopulation surviving initial treatment, emerges as a more effective strategy than awaiting the development of complete drug resistance, holding potential for curative cancer therapy. Based on our preliminary data on the upregulation of HER3 in DTPCs resistant to EGFR TKIs and the potent antitumor activity of EGFR-targeting chimeric antigen receptor (CAR)-T cells against DTPCs. We propose that HER3 is a promising target expressed on EGFR-TKI DTPCs and that CAR-T cells simultaneously targeting both EGFR and HER3 are an effective approach for targeting DTPCs with improved overall efficacy. In this proposal, we will evaluate HER3 as a therapeutic target for CAR-T cell therapy against EGFR-TKI DTPCs by validating its expression in DTPCs using in vitro cell models, in vivo xenograft and PDX models, and patient tissues. Additionally, we will evaluate the anti-tumor activity of HER3-targeting CAR-T cells against DTPCs. Subsequently, we will develop and characterize EGFRxHER3 bispecific CAR-T cells, evaluating their CAR expression, antigen binding affinity, and anti-tumor activity. We next will assess their anti-tumor efficacy in xenograft and PDX models to guide the selection of the most promising bispecific CAR-T cells for further development. If completed successfully, we will have EGFRxHER3 bispecific CAR-T cells ready for GMP-compliant clinical-grade CAR manufacturing, in preparation for clinical trial evaluation.